Body composition, muscle functionality and daily activity are clinically highly relevant parameters, because muscle function and daily activity are important contributors to the quality of life of a cancer patient. Furthermore, an improved physical condition of a patient, as reflected in body composition and physical performance, might contribute to its compliance to an anti-cancer therapy. E.g. the dose of chemotherapy can be provided as scheduled, instead of being adjusted to a lower body weight of the patient.
Cachexia is one of the most debilitating aspects of cancer and has been associated with increased morbidity and mortality, with a reduced quality of life, an impaired response to chemotherapy, an increased susceptibility to chemotherapy-induced toxicity and higher incidence of post-operative complications. Cancer cachexia can be defined as involuntary weight loss with a depletion of not only fat mass but also lean body mass due to muscle wasting. Symptoms besides mass loss are debilitation, weakness, edema, an impaired immune response and decline of motor and mental function. Cachectic patients have been shown to have higher resting energy expenditure which is not met by an increased nutrient intake, in many cases food intake is even reduced. Hence, approximately 45% of cancer patients loose more than 10% of their pre-diagnostic mass. The tumor can induce metabolic changes in protein metabolism, resembling those found in infection or injury. These changes are characterized by net protein breakdown and increased oxidation of branched-chain amino acids (BCAAs) in muscle to support energy supply and synthesis of gluconeogenic amino acids. The breakdown of host protein is partly stimulated by inflammatory mediators produced by the host (e.g. TNFα, IL-6)(1), but also by the tumor, through the release of a proteolysis inducing factor (PIF)(4). Moreover, the tumor has a high intrinsic protein synthesis rate and has the capacity for intracellular transport and catabolism of BCAAs.
An increased energy demand and an inflammatory catabolic status leads to an important reduction in body fat content and more worse muscle mass. It is therefore, hypothesized that nutritional support in cancer patients should aim more for counteracting net body protein breakdown, than for merely increasing caloric intake per se. In order to establish a new, positive balance in protein synthesis and breakdown, supplementation of protein should be combined with components modifying and mitigating the catabolic signal. A high amino acid supply has been described to be essential for increasing protein synthesis. BCAAs and especially leucine are known to control skeletal muscle protein metabolism by stimulating protein synthesis and inhibiting protein breakdown. Prospective caloric- and nitrogenous-controlled trials of BCAA supplementation via TPN in septic patients indeed resulted in an improvement of pre-albumin levels and decreased overall mortality in a patient group with a high Simplified Acute Physiology Score (LeGall-SAPS) classification. Supplementation of tumor-bearing rats with a diet supplemented with 3% leucine has been reported to reduce loss of lean body mass, gastrocnemius muscle mass and myosin content, when compared to an isonitrogenous and isocaloric control diet. These data are supported by the observation that leucine increased protein synthesis in pregnant tumor-bearing rats, possibly resulting from changes in the ubiquitin-proteasome system. Two clinical trials studied oral BCAA supplementation after surgical removal of the tumor and reported a shorter hospital stay, a better performance status at 3 months and an increased body mass at 1 year. BCAAs have also been supplemented in the presence of the tumor: patients undergoing chemotherapy received oral BCAA supplementation up to 1 year, resulting in a lower overall morbidity, improved nutritional status and better quality of life. Other nutrients which may have anti-cachectic effects are ω-3 polyunsaturated fatty acids (PUFAs). The vast majority of the clinical trials in which ω-3 PUFAs were tested report an increase or maintenance of body mass (BW); while in two clinical trials no effect on the loss of BW was found. In the latter, however, the supplementation period was only 2 weeks and/or included only a small number of patients. Other effects of EPA or fish oil supplementation in cancer patients, were a net lean tissue gain, an increase in total resting energy expenditure and physical activity level, a decrease in need for TPN and an improved quality of life, and even suggested improved survival.
WO 2004/026294 discloses nutritional compositions comprising a mixture of essential amino acids in free form and/or in salt form, rather than intact protein, for the promotion of muscle protein synthesis or controlling tumor-induced weight loss, such as cancer cachexia. Intact protein may be present in addition. However, a nutritional composition comprising at least 18 en % proteinaceous matter, at least part of which is whey protein, at least 12 wt. % leucine and an ω-3 polyunsaturated fatty acid selected from the group of eicosapentaenoic acid, docosahexaenoic acid, eicosatetraenoic acid and docosapentaenoic acid is not described in a single combination. Exemplified nutritional compositions comprise caseinate as protein source. In Example 2 of WO 2004/026294, it is concluded that ingestion of free essential amino acids is more effective than ingestion of a comparable amount of intact protein in stimulating net muscle protein synthesis.
EP 1 774 973 A1 discloses a composition comprising proteinaceous matter, said proteinaceous matter providing at least 24 en % and at least 12 wt % of leucine, based on total proteinaceous matter, for the treatment of insulin resistance. No compositions were exemplified.